Soluble frizzled-related protein 1 is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis.
It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker(-) c-kit(high) ScaI(+), hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms. We have now identified soluble Frizzled-related protein (sFRP)1 as an estrogen-inducible gene in stromal cells, whose expression corresponded to inability to support lymphopoiesis. Bone-lining stromal cells express sFRP1, and the transcripts were elevated by pregnancy or estrogen injection. Estrogen receptor-alpha was essential for both lymphoid suppression and induction of the sFRP family. SFRP1 has been mainly described as an antagonist for complex Wnt signals. However, we found that sFRP1, like Wnt3a, stabilized beta-catenin and blocked early lymphoid progression. Myeloerythroid progenitors were less affected by sFRP1 in culture, which was similar to estrogen with respect to lineage specificity. Hematopoietic stem cells expressed various Frizzled receptors, which markedly declined as they differentiated to lymphoid lineage. Thus, hormonal control of early lymphopoiesis in adults might partly relate to sFRP1 levels.
Yokota
Takafumi
T
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Oritani
Kenji
K
Garrett
Karla P
KP
Kouro
Taku
T
Nishida
Makoto
M
Takahashi
Isao
I
Ichii
Michiko
M
Satoh
Yusuke
Y
Kincade
Paul W
PW
Kanakura
Yuzuru
Y
D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011247:Pregnancy; D012995:Solubility; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D000099274:Frizzled-Related Proteins
D047628:Estrogen Receptor alpha; D006023:Glycoproteins; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins